14-74524043-A-G

Variant names:

• chr14-74524043-A-G
• rs862034
• NM_000428.3:c.2530+1081T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000428.3(LTBP2):​c.2530+1081T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 151,900 control chromosomes in the GnomAD database, including 31,859 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.65 (31859 hom., cov: 31)
• Consequence: LTBP2 NM_000428.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0590
• Publications: 42 publications found

Genes affected

LTBP2 (HGNC:6715): (latent transforming growth factor beta binding protein 2) The protein encoded by this gene belongs to the family of latent transforming growth factor (TGF)-beta binding proteins (LTBP), which are extracellular matrix proteins with multi-domain structure. This protein is the largest member of the LTBP family possessing unique regions and with most similarity to the fibrillins. It has thus been suggested that it may have multiple functions: as a member of the TGF-beta latent complex, as a structural component of microfibrils, and a role in cell adhesion. [provided by RefSeq, Jul 2008]

LTBP2 Gene-Disease associations (from GenCC):

• glaucoma 3, primary congenital, D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Weill-Marchesani syndrome 3

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital glaucoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glaucoma secondary to spherophakia/ectopia lentis and megalocornea

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP2	NM_000428.3	c.2530+1081T>C		intron_variant	Intron 15 of 35	ENST00000261978.9	NP_000419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP2	ENST00000261978.9	c.2530+1081T>C		intron_variant	Intron 15 of 35	1	NM_000428.3	ENSP00000261978.4
LTBP2	ENST00000556690.5	c.2530+1081T>C		intron_variant	Intron 15 of 34	5		ENSP00000451477.1
LTBP2	ENST00000553939.5	n.2530+1081T>C		intron_variant	Intron 15 of 35	5		ENSP00000452110.1

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98137 AN: 151780 Hom.: 31819 Cov.: 31

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.726

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.637

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.647 AC: 98229 AN: 151900 Hom.: 31859 Cov.: 31 AF XY: 0.645 AC XY: 47900 AN XY: 74236

African (AFR) AF: 0.671 AC: 27776 AN: 41418

American (AMR) AF: 0.636 AC: 9703 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2019 AN: 3470

East Asian (EAS) AF: 0.725 AC: 3730 AN: 5144

South Asian (SAS) AF: 0.625 AC: 3015 AN: 4826

European-Finnish (FIN) AF: 0.666 AC: 7025 AN: 10552

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.632 AC: 42902 AN: 67900

Other (OTH) AF: 0.636 AC: 1345 AN: 2116

Alfa AF: 0.636 Hom.: 97145

Bravo AF: 0.650

Asia WGS AF: 0.675 AC: 2350 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Benign	0.92
PhyloP100		-0.059
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs862034; hg19: chr14-74990746;